Dataset Information

Koeller2021 - PBPK model of ICG liver function tests

ABSTRACT: Physiollogically based pharmacokinetic (PBPK) model of indocyanine-green (ICG) liver function tests.

SUBMITTER: Matthias König

PROVIDER: MODEL2301090001 | BioModels | 2023-01-18

REPOSITORIES: BioModels

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Publications

Prediction of Survival After Partial Hepatectomy Using a Physiologically Based Pharmacokinetic Model of Indocyanine Green Liver Function Tests.

Köller Adrian A Grzegorzewski Jan J Tautenhahn Hans-Michael HM König Matthias M

Frontiers in physiology 20211122

The evaluation of hepatic function and functional capacity of the liver are essential tasks in hepatology as well as in hepatobiliary surgery. Indocyanine green (ICG) is a widely applied test compound that is used in clinical routine to evaluate hepatic function. Important questions for the functional evaluation with ICG in the context of hepatectomy are how liver disease such as cirrhosis alters ICG elimination, and if postoperative survival can be predicted from preoperative ICG measurements. ...[more]

PMID: 34880771

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Project description:The Göttingen Minipig is gaining ground as nonrodent species in safety testing of drugs for pediatric indications. Due to developmental changes in pharmacokinetics (PK) and pharmacodynamics (PD), physiologically-based pharmacokinetic (PBPK) models are built to better predict drug exposure in children and to aid species selection for nonclinical safety studies. These PBPK models require high quality physiological and PK/PD data such as protein abundance of drug metabolizing enzymes. These data are available for man and rat, but scarce for the Göttingen Minipig. The aim of this study was to assess hepatic cytochrome P450 (CYP) protein abundance in the developing Göttingen Minipig by using mass spectrometry. In addition, sex-related differences in CYP protein abundance and correlation of CYP enzyme activity with CYP protein abundance were assessed. The following age groups were included: gestational day (GD) 84 - 86 (n = 8), GD 108 (n = 6), postnatal day (PND) 1 (n = 8), PND 3 (n = 8), PND 7 (n = 8), PND 28 (n = 8) and adult (n = 8). Liver microsomes were extracted and protein abundance was compared to that in adult animals. Next, the CYP protein abundance was correlated to CYP enzyme activity in the same biological samples. In general, CYP protein abundance gradually increased during development. However, we observed a stable protein expression over time for CYP4A24 and CYP20A1 and for CYP51A1, a high protein expression during the fetal stages was followed by a decrease during the first month of life and an increase towards adulthood. Sex-related differences were observed for CYP4V2_2a and CYP20A1 at PND 1 with highest expression in females for both isoforms. In the adult samples, sex-related differences were detected for CYP1A1, CYP1A2, CYP2A19, CYP2E1_2, CYP3A22, CYP4V2_2a and CYP4V2_2b with higher values in female compared to male Göttingen Minipigs. The correlation analysis between CYP protein abundance and CYP enzyme activity showed that CYP3A22 protein abundance correlated clearly with the metabolism of midazolam at PND 7. These data are remarkably comparable to human data and provide a valuable step forward in the construction of a neonatal and juvenile Göttingen Minipig PBPK model.

Project description:Basic PBPK (Physiologically Based PharmacoKinetic) model of Acetaminophen. This is a basic model of Acetaminophen (APAP, Paracetamol) pharmacokinetics in humans. Many of the model parameters (compartment volumes, volumetric flow rates, etc.) are scaled allometrically based on the body weight (BW) raised to the 3/4 power. Because of that, the assigned values of many of the parameters are recalculated at run time and are different than the default values for the particular entity (e.g., the volume of a compartment and the volumetric flow rate between compartments). APAP dose is initially given in grams (APAP_Dose_gram), which is converted to moles via the APAP molecular weight (APAP_MW). APAP quantities throughout the rest of the models are given in moles. The base parameters are for a 70Kg human and a pharmacological oral dose of 1.4 gram of APAP. Metabolism is modelled as a single ODE in the liver compartment and the metabolite does not leave that compartment. This model is loosely based on the model of Wambaugh and Shaw (PLoS Comput Biol. 2010 Apr 22;6(4):e1000756. doi: 10.1371/journal.pcbi.1000756. Pubmed ID: PMID- 20421935) with the following changes: The lung lumen compartment was omitted. A kidney compartment was added. Glomerular Filtration is from the kidney compartment. The APAP dose was changed to 1.4g. The gut adsorption rate constant (KGutabs), tissue partition coefficients and liver metabolism rate constant (CLmetabolism) were fit using the human in vivo data of Critchley (Critchley, J. A., Critchley, L. A. H., Anderson, P. J., and Tomlinson, B. 2005 Journal of clinical pharmacy and therapeutics, 30(2), 179-184). To model the extensive re-adsorption of APAP from the kidney tubules back into the blood the QGfr value is modified. This was done by changing the scaling parameter QGFR_ref value from 0.31 to 0.039, resulting in a decrease in the QGfr value of 8 fold (from 7.2 L/hr to 0.91 L/hr). The parameters in this file are the REFSIM parameters from our publication.

Dataset Information

Koeller2021 - PBPK model of ICG liver function tests

Publications

Prediction of Survival After Partial Hepatectomy Using a Physiologically Based Pharmacokinetic Model of Indocyanine Green Liver Function Tests.

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